Non-steroidal anti-inflammatory drugs (NSAIDs), which have been clinically widely used as pharmaceuticals having excellent analgesic, anti-inflammatory, and antipyretic effects, account for about 5% of all prescription drugs in Japan.
NSAIDs suppress generation of prostaglandins (PGs), for example, PGE2, by the inhibitory action on cyclooxygenase (COX) activity and thus exhibit an excellent anti-inflammatory effect. NSAIDs, however, have strong gastrointestinal side effects.
Since PGE2 has a strong protective action on the gastrointestinal mucosa, it has been considered that the gastrointestinal side effect of NSAIDs is based on the inhibitory action on COX activity.
Of COX subtypes, particularly COX-1 and COX-2 are main enzymes involved in the inflammation activity of COX in the gastrointestinal mucosa or tissues. Because of this, selective inhibitors of COX-2 activity can reduce side effects in the stomach and duodenal site (Non-Patent Literature 1).
However, these selective inhibitors of COX-2 activity have been recently reported to impose a potential risk of thrombosis on the cardiovascular system, such as myocardial infarction (Non-Patent Literatures 2 and 3).
Since prostacyclins having strong platelet aggregation inhibitory and vasodepressor effects are mainly produced by selective inhibitors of COX-2 activity, from the above viewpoint, development of NSAIDs having no gastrointestinal side effects and being independent of selective inhibitors of COX-2 activity has been needed under present circumstances.
The present inventors have showed that apoptosis by NSAIDs independent of COX was found in NSAID-induced gastric tissues and direct cytotoxicity of NSAIDs is based on the gastric mucosa permeability (Non-Patent Literatures 4 and 5). As a result, the present inventors have proposed that NSAIDs with low gastric mucosa permeability are independent of selective COX-2 inhibitory activity and safe to the gastric tissues.
Loxoprofen (1) described below has been widely clinically used as a NSAID independent of selective inhibitory action on COX-2 activity and been safer than indomethacin, which has been used as a common NSAID. Loxoprofen (1) is accordingly a standard anti-inflammatory drug in Japan.
Loxoprofen (1), so-called prodrug, is absorbed in a gastrointestinal tract site and then converted to its active form trans-alcohol in vivo. Loxoprofen (1) has lower mucosa permeability activity than other NSAIDs and can be also called a leading compound for searching a compound that is less involved in ulceration in the gastrointestinal mucosa.
According to such a point of view, the present inventors have provided 2-fluoroloxoprofen (2) described below in which a fluorine atom is introduced to the 2-position of loxoprofen (1). The present inventors have confirmed that this 2-fluoroloxoprofen has a low ulceration action and to have the same anti-inflammatory effect as loxoprofen. The patent application on compounds including 2-fluoroloxoprofen has already been filed (Patent Literature 1).

The present inventors have further studied on 2-fluoroloxoprofen derivatives and as a result, have successfully synthesized compounds which have more excellent anti-inflammatory and analgesic effects while avoiding side effects such as gastrointestinal disorders caused by ulcerogenesis, to thereby complete the present invention.